Wake Forest University, Winston Salem, NC

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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

Wake Forest University, Winston Salem, NC

SAMUEL A. DEADWYLER - Primate Testing - 2007

Grant Number: 1R01DA023573-01
Project Title: Neuronal Analysis of Cocaine Effects on Cognition
PI Information: PROFESSOR AND VICE-CHAIR, SAMUEL A. DEADWYLER, [email protected]    

Abstract: DESCRIPTION (provided by applicant): The purpose of this research project is to assess the manner in which information processing in brain structures of nonhuman primates is re-organized by the introduction of and sustained exposure to cocaine as a reinforcer for complex cognitive tasks. It has long been implicitly assumed in analyses of human drug addiction that substances which are abused somehow take over normal reinforcement mechanisms in the brain, diverting such "reward pathways" to the control of drug seeking activities. Using a well-characterized short-term memory/executive function paradigm (multi-object delayed match to sample [DMS] task) studies will determine how cognitive processing is affected by acute and longterm exposure to cocaine as a reinforcer in this task. This primate model of cognitive function has been characterized in recent PET imaging and electrophysiological recording studies from this laboratory. On the basis of that work three important brain regions, medial temporal lobe (MTL), dorsal prefrontal cortex (DPFC) and the dorsal and ventral striatum (D/VStr), shown to be engaged during task performance, will be assessed for effects of cocaine on cognitive processing. Aim 1 will determine neuronal firing characteristics in these three brain regions associated with performance of the DMS task and will identify single neuron correlates of low vs. high cognitive load trials. Aim 2 will examine how these neural correlates change when the task is performed for cocaine injections delivered as the trial reinforcer in comparison to normal appetitive (juice) rewards. Aim 3 will extend the above analyses to animals that are repeatedly exposed to conditions in which cocaine and juice reinforcers are implemented in the same random manner during day-to-day testing for a period of six months in order to assess cumulative changes in DMS responding and associated neuronal correlates over a time period in which performance is sustained at criterion levels by both reinforcers. The final Aim 4 will assess the effects of stress on cocaine vs. juice reinforced DMS performance and associated neural correlates of cognitive load (Aim 1), induced by a method of sleep deprivation perfected for nonhuman primates in this laboratory. Relevance: In a society that is evolving more and more toward increased stress and demand on its citizens the individual level of cocaine abuse is a major health care problem. Such behavior eventually results in inability of the addict to cope with the complex nuances of a complex technologically-based work place. Turning to drugs is a natural course of action for pressured, overworked and under employed personnel.How cocaine use advances to addiction in this context is directly related to effects on cognition, reasoning and decision making. Therefore understanding how cocaine modulates and gradually over time eliminates effective cognitive processing, as studied here, is of primary importance in the prevention of drug addiction.

Public Health Relevance: This Public Health Relevance is not available.

Thesaurus Terms: There are no thesaurus terms on file for this project.

Institution:
WAKE FOREST UNIVERSITY HEALTH SCIENCES
MEDICAL CENTER BLVD
WINSTON-SALEM, NC 27157
Fiscal Year: 2007
Department: PHYSIOLOGY AND PHARMACOLOGY
Project Start: 01-SEP-2007
Project End: 31-JUL-2012
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: NMB

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

Sam A. Deadwyler,1 Linda Porrino,1 Jerome M. Siegel,2 and Robert E. Hampson1 1Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, and 2Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California Veterans Administration Greater Los Angeles Healthcare System/Sepulveda, North Hills, California 91343

The Journal of Neuroscience, December 26, 2007, 27(52):14239-14247

Defense Advanced Research Projects Agency (DARPA) Grants DAAD19-02-1-0060 (Army Research Office) (S.A.D., L.P.) and BAA 04-12-F9034, National Institutes of Health Grants DA00119 and DA06634 (S.A.D., L.P.), DA09085 (L.P.), and NS14610 and MH64109 (J.M.S.)

Subjects.
Eight adult male rhesus monkeys (Macaca mulatta) weighing (8.0�11.0 kg) were used in this study. They were individually housed in stainless steel cages in temperature and humidity controlled colony rooms with lighting maintained on a 6:00 A.M/6:00 P.M. on/off schedule and fed a diet of monkey chow supplemented by fresh fruit to maintain daily monitored body weight. Fluid intake was restricted in time and amount such that a prescribed volume of an animal's normal daily fluid intake (80 ml/kg) was received either during the behavioral testing session, or within 2 h of being returned to the home cage.

Behavioral Testing.
Each monkey was exposed to six different testing conditions [Normal Vehicle, Alert orexin-A (i.v. and nasal), Sleep Deprivation, Sleep Deprivation + orexin-A (i.v. or nasal)], which required 11�14 test sessions for each of the eight monkeys. Animals were placed in a primate chair 1.5 m in front of an LCD-front-projection screen for daily testing on a multi-image visual delayed match-to-sample (DMS) task and performed 150�300 trials per session (Hampson et al., 2004; Porrino et al., 2005). Animals were trained to move a cursor tracked by a fluorescent marker attached to the back of the monkey's hand into the images by positioning the hand within a two dimensional coordinate system on the chair counter. Stimuli consisted of clip art images projected as 25 cm squares within a 3 x 3 position matrix onto a 1.0 x 1.0 m display. All images were unique to a particular trial during a session and no image was exposed on more than on one trial per session. Responses to appropriate stimuli were rewarded with diluted fruit juice delivered via a sipper tube placed in front of the mouth. All animals were trained to a stable baseline on the DMS task in which delay varied randomly from 1 to 90 s on a given trial, and the number of non-match stimuli (images) varied randomly from 1 to 7 in the Match phase of the task. As shown previously performance accuracy varied directly with duration of delay and number of non-match images (#images) presented in the Match phase (Hampson et al., 2004; Porrino et al., 2005). Sets of stimulus images were routinely changed every 2 weeks to maintain the trial-unique feature of each session. Animals performed the task on consecutive days each week.

Sleep Deprivation Procedure.
Sleep deprivation consisted of 30�36 h of continuous sleep prevention and wakefulness supervised continuously by laboratory personnel as previously verified using EEG recordings of sleep architecture. On sleep deprivation nights animals were maintained in a cage separate from their home cage in a continuously lighted room and kept awake with videos, music, occasional treats, gentle cage shaking, and interaction with technicians (working in 3 h shifts) through the night, until the usual daily testing time the next day. After testing animals were returned to their home cage and allowed to sleep. In a previous investigation (Porrino et al., 2005) evidence was provided that changes in brain imaging correlates of local glucose utilization during the DMS task (see below) were consistent with simultaneously recorded EEG changes produced by 30�36 h of sleep deprivation. Hence, replication of the same brain imaging correlates of sleep deprivation in this study verified that each animal was tested in the same sleep loss condition as reported preciously. Intervals of 10 d, mandated by IACUC regulations, were interspersed between sleep deprivation episodes for each animal. There were no residual effects of the 30�36 h sleep deprivation regimen on testing 24 h afterward at which time animals had returned to their normal sleep patterns.

Please email:  SAMUEL A. DEADWYLER, [email protected] to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: [email protected]

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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